Overcome And Avoid Pgp Mediated MDR With A Gold-based Nanoconstruct

Cancer multidrug resistance (Multidrug Resistance, MDR) has been a major obstacle in cancer chemotherapy, especially in lung cancer in which90percent faliure or relapse were due to MDR. So overcoming cancer MDR is an urgent issue in cancer therapy.MDR is a phenomenon that resistance to one drug make cancer cell unsensitive to a list of anticancer drugs which are structurally uncorrelated. It is believed to be a self-protection behavior of cancer. Several mechanisms are aboarded to account for MDR:increased efflux, decreased infflux, activation of detoxifying systems, activation of DNA repair, blocked apoptosis and etc. While P-glycoprotein (P glycoprotein, Pgp), a member of ABC transportor family encoded by MDR1gene, mediated drug efflux is the most important one. Pgp is a transmembrane protein which could transfer harmful organic molecular out of cells. Pharmacy studies show that a lot of anticancer drugs such as paclitaxel, doxrubicin have been proved to be substrates of Pgp. Overexprssion of Pgp on cancer cells significantly decrease the concentration of anticancer drug inside cancer cells, which make cancer cell unsensitive to anticancer drugs.So efficient delivery of drugs into cancer cells is the key to overcome Pgp mediated MDR.The question why Pgp on cancer cells would be overexpressed after chemtherapy is still bothering us since various cellular molecule change during this peroid. However, the activation of MDR1gene is treated as the leading cause of Pgp overexpression. The acquired MDR theory attribute this to the unstability of cancer genes:a depressed cancer microenvironment bulided by the long-termed and high concentration of anticancer drugs stimulate or influence various signalling pathways inside cancer cells which finally activate MDR1gene to overexpress Pgp. The intrinsic MDR theory see MDR as a result of selection:the subpopulation in cancer cells with Pgp overexpressed existed at the beginning of cancer would always survive and proliferate even after chemtherapy which finally results in MDR. However, more and more studies suggested MDR as an much more intricate phenomenon with the above both theory included in.To overcome Pgp mideated MDR, several strategies have been clinical used or studied in lab:drug combination, improved drug administration, new anticancer drugs, Pgp inhibitor, gene silence technology and etc. However, all the above methods are not successful as expection owe to high side effect, low efficiency, high spending and unstability. Further more, acquired MDR is the focus of the above existing methods, which is far from enough. Therefore, a novel tactics concern about both acquired and intrinsic MDR is urgent at this moment.Nano-drug delivery system (DDS) is a developing technology using nanomaterials as drug carriers to deliver drugs into disease section. Nanomaterials, as the most promising materials, show great application advantages in bioscicence such as biocompatibility, flexibility, capacity, diversity and etc. Moreover, DDS shows its unique power in cancer therapy:EPR effect, targeting ability, controlled drug release, combination therapy and etc. DDS is able to transmit anticancer drugs into resistant cancer cells and change the concentration and the distribution of drugs inside and outside cancer cells at the same time which might give a way to overcome and avoid Pgp mediated MDR.In this study, we reported a novel nanoconstruct (PPGNP) based on gold nanoparticles which functinalized with PEG ligands and drug carrier ligands β-CD to embed paclitaxel (PTX). PPGNP could deliver PTX into resistant cancer cells with Pgp overexpression efficiently to overcome acquired Pgp mediated MDR. And unresistant cancer cells showed no obvious Pgp upregulation after long-term PPGNP treatment compared with PTX treatment which suggested the ability of avoiding Pgp mediated MDR of PPGNP. This study give a word to the promising application of NDS in cancer therapy especially in cancer MDR therapy.